Platinum-based drugs find widespread use in the treatment of cancer. Cisplatin, carboplatin and oxaliplatin, for example, are used extensively in the treatment of a range of solid tumors including bladder cancer, breast cancer, colon cancer, head and neck cancer, small cell and non-small cell lung cancer, ovarian cancer, melanoma and non-Hodgkin lymphoma. The efficacy and applicability of platinum drugs, however, are limited by systemic toxicity and drug resistance with significant relapse and progression rates being observed amongst patients.
Resistance to platinum drugs is believed to be multi-faceted (Shen, et al., 2012, Pharmacological Reviews, 64:706-721). Upregulation of CD44 and/or the presence of cancer stem cells has been observed in a number of platinum drug-resistant cancers, including for example, ovarian cancer (see, for example, Pylväs-Eerola, et al., 2016, Anticancer Res., 36:3425-3432; Gao, et al., 2015, Oncotarget, 6:9313-9326), head and neck cancer (see, for example, Kulsum, et al., 2016, Mol. Carcinog. doi: 10.1002/mc.22526) and lung cancer (see, for example, Leung, et al., 2010, PLoS One, 5: e14062-10). Alterations in glycosylation patterns have also been reported (Ferreira, et al., 2015, Drug Resistance Updates, 24:34-54).
Glycosaminoglycans (GAGs) are carbohydrate modifications attached to cellular and extra-cellular proteins. Changes in expression and composition of GAGs have been sporadically reported in bladder cancer over the past three decades (De Klerk, 1985, J Urol., 134:978-81; Hennessey, et al., 1981, Cancer Res., 41:3868-73; Ohyama, 2008, International Journal of Clinical Oncology, 13:308-13). Chondroitin sulfate (CS) is a major cancer-associated GAG, which also plays a key role in malaria pathogenesis (Rogerson, et al., 1995, J Exp. Med., 182:15-20). The malaria parasite Plasmodium falciparum has evolved a protein VAR2CSA that mediates attachment of infected erythrocytes to a distinct type of chondroitin sulfate (CS) chain in the placental syncytium (Salanti, et al., 2004, JExp. Med., 200:1197-203). CS chains are comprised of alternating glucoronic acid and N-acetylgalactosamine (GalNAc) residues that vary in chain length and sulfation pattern. Although not fully resolved, placental-type CS is likely comprised of dense patches of carbon-4 GalNAc sulfations (Alkhalil, et al., 2000, J Biol Chem., 275:40357-64; Beeson, et al., 2007, J Biol Chem., 282:22426-36). This particular CS signature is required for exclusive sequestration of VAR2CSA+ erythrocytes to placenta giving rise to pregnancy-associated malaria in endemic regions of the world (Salanti, et al., 2004, ibid.; Fried and Duffy, 1996, Science, 272:1502-4). Many tumors express placental-type CS as a secondary oncofetal CS (ofCS) modification, which can be specifically recognized by recombinant malarial VAR2CSA (rVAR2) proteins (International Patent Publication No. WO 2013/117705; Salanti, et al., 2015, Cancer Cell, 28:500-14).
Functional binding fragments of VAR2CSA and their use in the treatment of conditions associated with the expression of chondroitin sulfate A (CSA) have been described (International Patent Publication No. WO 2013/117705). VAR2CSA-drug conjugates and their use in the treatment of cancer and other diseases have also been described (International Patent Publication No. WO 2015/095952).
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present disclosure. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the claimed invention.